Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease characterized by an increased left ventricular mass in the absence of another cause for hypertrophy. This disease provides a model to study the process of cardiac hypertrophy. In approximately 15% of affected families, the disease gene encodes a beta myosin heavy chain (BMHC) gene with a missense mutation. We have identified 32 distinct mutations in the BMHC gene and mapped them onto the 3D structure of the head of skeletal myosin. The mutations cluster in 4 regions, suggesting different types of interference in the actomyosin cross-bridge kinetics as a function of mutation location. We have studied the mechanical properties of extracted mutant myosins and muscle fibers expressing these myosins, to analyze the pathophysiology at a molecular level. One of the clusters of mutations led us to the discovery of mutations in the myosin light chains which cause a variant of HCM characterized by an obstruction in the middle of the left ventricle. Through a series of arguments, the association of the myosin light chain mutations with the rare subtype of HCM led us to hypothesize the importance of the "stretch-activation response" to the function of the normal heart. The stretch-activation response in Drosophila flight muscle has been previously shown to be distorted by a mutation in the "regulatory" myosin light chain (RLC), resulting in flightless flies whose wings do not beat properly. We have developed transgenic mice expressing the mutant myosin "essential" light chain (ELC), from a patient with cardiac hypertrophy. The hearts from these mice also do not beat properly. That is, there is a shift of the frequency of maximum power output to a rate beyond the physiologic range, with consequent loss of oscillatory power. We have cloned the human enzyme that phosphorylates the RLC and and identified a genetic mutation in a small family. This mutant enzyme has been expressed and shown to have an increased maximum velocity compared to the normal enzyme. We have performed mechanical studies on isolated muscle fibers treated with this cloned enzyme and demonstrated a change in the stretch-activation response. We are continuing to use muscle fibers from normal and transgenic mice to study the basic biophysical response of muscle fibers to light chain phosphorylation.